THE ROLE OF RAMPS IN LIGAND-ENGENDERED SIGNAL BIAS OF SECRETIN-LIKE RECEPTORS
Lead Research Organisation:
Aston University
Department Name: Sch of Life and Health Sciences
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Planned Impact
The research that we propose will have a broad range of impacts from advancement of fundamental scientific knowledge to training of a highly skilled workforce.
Advancement of scientific knowledge: Our research program will develop knowledge that will enhance our understanding of GPCR pharmacology. The secretin family GPCRs are important therapeutic targets for a host of disorders including diabetes, obesity, cardiovascular disease, neurodegenerative disorders. The incretins (GLP-1, glucagon and GIP) form a significant proportion of the secretin receptor family. These molecules have been targeted for treatments related to diabetes and obesity. To date, incretin-based therapeutics generates in excess of $1 billion annually and consequently, there is considerable interest in developing the next generation of diabetic drugs. Our investigations into RAMP association with secretin receptors will aid this research. Any novel biological data generated will yield new knowledge that will be disseminated through international journals, conference publications, seminars, collaborative contacts with other researchers and participation in professional body events.
Pharmaceutical and Biotechnology industries: The UK economy relies heavily on the Pharmaceutical and Biotechnology industry; it employs more than 250,000 people and generates billions of pounds annually. Drug discovery relies extensively on a strong basic-science background to provide insights into potential drug targets and the development of new assays and technologies. Our work, systematically analysing one entire family of GPCRs, will contribute to this knowledge base and is backed by industry. Our data will eventually aid in the design of more efficacious and effective drugs targeting the secretin receptor family. This will be highly relevant not only to "big pharma", but also to regional businesses in the Midlands.
Translational medicine: Our work has the potential to contribute to significantly improved efficacy and reduced treatment costs for diseases associated with many GPCR-based diseases. Thus our work is likely to impact positively on the economics of the health care sector over the longer-term.
Provision of skilled workforce: The PDRA (Dr Weston) and the research technician working on this project will be trained in a wide range of pharmacology techniques. These skills are highly specialised and valuable, and will equip them for careers in academia or industry. Dr Weston will be encourage to attend courses held at the University of Warwick's Centre for Lifelong Learning provides a range of courses to further aid members of staff in their professional development. Dr Weston will be encourage to attend these courses and also to enrol on the Postgraduate Certificate in Academic and Professional Practice (PCAPP). Further, Warwick and Aston provide a range of transferable skills courses designed to maximise individual potential and employability. Thus our work will contribute to the economic competitiveness of the UK through the provision of highly skilled labour.
The general public: We will disseminate our findings to the general public at the earliest juncture. WMS has an active public engagement policy and an excellent track record in outreach activities. We will host yearly public lectures for local secondary school teachers from around the Midlands at WMS. These events will be aimed at enthusing school children from aged 11-13 in the "Science of Cells". Public lectures on the importance and implications of our science will be given through Café de Scientifique a forum for debating science issues, promoting public engagement and making science accountable. Articles will also be produced for community newsletters. We will also develop a project webpage and podcasts aimed specifically at the lay audience to explain our science and its medical benefits.
Advancement of scientific knowledge: Our research program will develop knowledge that will enhance our understanding of GPCR pharmacology. The secretin family GPCRs are important therapeutic targets for a host of disorders including diabetes, obesity, cardiovascular disease, neurodegenerative disorders. The incretins (GLP-1, glucagon and GIP) form a significant proportion of the secretin receptor family. These molecules have been targeted for treatments related to diabetes and obesity. To date, incretin-based therapeutics generates in excess of $1 billion annually and consequently, there is considerable interest in developing the next generation of diabetic drugs. Our investigations into RAMP association with secretin receptors will aid this research. Any novel biological data generated will yield new knowledge that will be disseminated through international journals, conference publications, seminars, collaborative contacts with other researchers and participation in professional body events.
Pharmaceutical and Biotechnology industries: The UK economy relies heavily on the Pharmaceutical and Biotechnology industry; it employs more than 250,000 people and generates billions of pounds annually. Drug discovery relies extensively on a strong basic-science background to provide insights into potential drug targets and the development of new assays and technologies. Our work, systematically analysing one entire family of GPCRs, will contribute to this knowledge base and is backed by industry. Our data will eventually aid in the design of more efficacious and effective drugs targeting the secretin receptor family. This will be highly relevant not only to "big pharma", but also to regional businesses in the Midlands.
Translational medicine: Our work has the potential to contribute to significantly improved efficacy and reduced treatment costs for diseases associated with many GPCR-based diseases. Thus our work is likely to impact positively on the economics of the health care sector over the longer-term.
Provision of skilled workforce: The PDRA (Dr Weston) and the research technician working on this project will be trained in a wide range of pharmacology techniques. These skills are highly specialised and valuable, and will equip them for careers in academia or industry. Dr Weston will be encourage to attend courses held at the University of Warwick's Centre for Lifelong Learning provides a range of courses to further aid members of staff in their professional development. Dr Weston will be encourage to attend these courses and also to enrol on the Postgraduate Certificate in Academic and Professional Practice (PCAPP). Further, Warwick and Aston provide a range of transferable skills courses designed to maximise individual potential and employability. Thus our work will contribute to the economic competitiveness of the UK through the provision of highly skilled labour.
The general public: We will disseminate our findings to the general public at the earliest juncture. WMS has an active public engagement policy and an excellent track record in outreach activities. We will host yearly public lectures for local secondary school teachers from around the Midlands at WMS. These events will be aimed at enthusing school children from aged 11-13 in the "Science of Cells". Public lectures on the importance and implications of our science will be given through Café de Scientifique a forum for debating science issues, promoting public engagement and making science accountable. Articles will also be produced for community newsletters. We will also develop a project webpage and podcasts aimed specifically at the lay audience to explain our science and its medical benefits.
People |
ORCID iD |
David Poyner (Principal Investigator) |
Publications
Hay DL
(2018)
Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25.
in British journal of pharmacology
Routledge S
(2017)
The effects of RAMPs upon cell signalling
in Molecular and Cellular Endocrinology
Watkins HA
(2016)
Receptor Activity-modifying Proteins 2 and 3 Generate Adrenomedullin Receptor Subtypes with Distinct Molecular Properties.
in The Journal of biological chemistry
Weston C
(2015)
Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).
in The Journal of biological chemistry
Weston C
(2016)
Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors.
in The Journal of biological chemistry
Winfield I
(2022)
The Role of ICL1 and H8 in Class B1 GPCRs; Implications for Receptor Activation
in Frontiers in Endocrinology
Woolley M
(2017)
Receptor activity-modifying protein dependent and independent activation mechanisms in the coupling of calcitonin gene-related peptide and adrenomedullin receptors to Gs
in Biochemical Pharmacology
Woolley MJ
(2017)
Understanding the molecular functions of the second extracellular loop (ECL2) of the calcitonin gene-related peptide (CGRP) receptor using a comprehensive mutagenesis approach.
in Molecular and cellular endocrinology
Description | We have shown that the properties of cell surface receptors are altered when they associate with accessory proteins known as receptor activity modifying proteins (RAMPs). Many of these receptors are important in diabetes; the association with RAMPs creates new drug targets for the treatment of this disease. We have also shown that RAMPs have profound influences on the properties of receptors that respond to calcitonin gene-related peptide and allied peptides. In this case, the RAMPs "steer" the receptor to different signalling systems within a cell, depending on how they are activated. This raises the possibility of being able to target only the signalling pathways relevant to disease, not those which might be important for other processes within the cell. Previously RAMPs were largely considered just to influence the way in which hormones and nerve transmitters bound to cells; we have shown that their predominant effect is on how these agents activate cells. |
Exploitation Route | These finding should eventually result in new drugs to treat diabetes and cardiovascular diseases. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
URL | https://research.aston.ac.uk/portal/en/persons/david-poyner(0bb31ffe-dec2-4b93-864b-7b6933d16fd8).html |
Description | The findings are being explored to develop new therapeutic antibodies that can target receptor-RAMP complexes. This has resulted in an BBSRC IPA to myself, Prof Mark Wheatley (Coventry University) and Prof Tim Dafforn (Birmingham University) and UCB. We are also collaborating with an SME to investigate the roles of RAMPs in ligand bias on heart cells, with the eventual aim of developing new agents to treat heart failure |
First Year Of Impact | 2018 |
Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | Internal PhD studentship |
Amount | £30,000 (GBP) |
Organisation | Aston University |
Department | School of Life and Health Sciences |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2016 |
End | 08/2019 |
Description | MIPTP CASE award |
Amount | £66,600 (GBP) |
Organisation | Midlands Integrative Biosciences Training Partnership |
Sector | Academic/University |
Country | United Kingdom |
Start | 10/2021 |
End | 09/2024 |
Description | CLR and congenital birth defects |
Organisation | University of North Carolina at Chapel Hill |
Country | United States |
Sector | Academic/University |
PI Contribution | We have modelled a naturally occurring mutated form of the calcitonin receptor-like receptor which prevents its association with birth defects and leads to fatal birth defects |
Collaborator Contribution | Our partners identified the initial birth defect in clinical studies and have explored its phenotype in cellular and whole-organism models. |
Impact | Paper in preparation |
Start Year | 2017 |
Description | Collaboration with UCB |
Organisation | UCB Pharma |
Department | UCB Celltech |
Country | United Kingdom |
Sector | Private |
PI Contribution | We have supplied SMALP-solubilised GPCRs for antibody production; we are currently expanding this to RAMP-receptor complexes |
Collaborator Contribution | UCB are currently using our material to produce antibodies |
Impact | This lead to an application for a new project grant to the BBSRC and also resulted in the award of a university awarded PhD studentship. |
Start Year | 2015 |
Description | Role of RCP in promoting signalling at GPCRs |
Organisation | University of Rochester |
Country | United States |
Sector | Academic/University |
PI Contribution | We have been examining the ability of receptor component protein (RCP) to facilitate G-protein coupling to receptor/RAMP complexes using siRNA |
Collaborator Contribution | Dr Dickerson of Rochester has supplied us with his antibody directed against RCP |
Impact | None so far |
Start Year | 2016 |
Description | Article in community magazine describing recent research |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Some comments that the article was interesting I was subsequently invited to speak about my work, to a community group |
Year(s) Of Engagement Activity | 2015 |
Description | Article in community magazine on the importance of scientific evaluation |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | There were a few positive comments, but generally limited response Difficult to say! |
Year(s) Of Engagement Activity | 2015 |
Description | New ways of looking at GPCRs |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Project website This has lead to several enquiries for PhD places |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.aston.ac.uk/lhs/staff/az-index/poynerdr/ |
Description | Press release (Glucagon and RAMPs) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | A press release was issued to highlight the significance of how RAMP2 modulates the action of glucagon. This is important for the treastment of diabetes. This resulted in discussion with colleagues at scientific meetings in September and December |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.phar.cam.ac.uk/news/GrahamLadds |
Description | Protein modelling master class |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Students from local schools visit the university and learn how to design drugs that bind to proteins using molecular modelling |
Year(s) Of Engagement Activity | 2016,2017 |
Description | Protein modelling masterclass |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Hands-on demonstration of protein modelling and its application in drug discovery to 6th formers |
Year(s) Of Engagement Activity | 2017 |
Description | Seminar at Department of Pharmacology, Cambridge |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Talk in front of researchers and undergraduate students of pharmacology at Cambridge |
Year(s) Of Engagement Activity | 2017 |
Description | Talk at 2016 SMALP users meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This was a 20 minute talk on the use of SMALPs for solubilising GPCRs |
Year(s) Of Engagement Activity | 2016 |
Description | Talk at village group |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I spoke about my work as a scientist to "Catalyst", a social group at Highley, close to where I live |
Year(s) Of Engagement Activity | 2016 |
Description | Talk at village group |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Talk to around 15 people at group in the village of Highley about my work as scientist |
Year(s) Of Engagement Activity | 2017 |
Description | Talk to community group |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | There was a lot of discussion following the talk I was asked if a 6th former could spend a day in my lab, by a the friend of his parent, who attended the talk. This visit took place on 2-11-15 |
Year(s) Of Engagement Activity | 2015 |
Description | Talks for ELRIG at Lab Innovations exhibition, Birmingham |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Significant discussions after the talk Two new potential collaborations are being explored |
Year(s) Of Engagement Activity | 2015 |